Phenylglycine racemization in Fmoc-based solid-phase peptide synthesis: Stereochemical stability is achieved by choice of reaction conditions

Chen, Liang; Behnam, Mira A. M.; Sundermann, Tom R.; Klein, Christian D.

doi:10.1016/j.tetlet.2017.04.047

Cited by 48 publications

(39 citation statements)

References 23 publications

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“…Another possible reason for the lack of the derivatives’ hydrolysis was the inability of their ester moieties to enter the hydrolytic site of the enzyme, which could have been caused by racemization of the Phg that has been previously detected in similar conditions of solid‐phase peptide synthesis or steric hindrance as it could be in the case of tert ‐butyl derivatives . However, one of the stereoisomers should still fit the enzyme hydrolytic pocket and, at least, partial hydrolysis should take place.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

et al. 2019

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Recent studies indicate that tubulin can be a host factor for vector‐borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub‐micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

et al. 2019

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“…3 Through the careful selection of activation and coupling conditions, it is possible to generate peptides (such as GPA precursor peptides) using Fmoc synthesis. [9][10][11] However, the requirement to synthesise peptide CoA species for PCP loading adds a further complication, as the generation of the C-terminal thioester necessitates either activation and coupling or thioester exchange, both of which have high potential to racemise the C-terminal residue. This is particularly problematic in the case of GPAs (the terminal Dpg residue) 4 or b-lactam antibiotics such as nocardicin (the terminal Hpg residue), where the stereochemistry of this residue plays an important role in subsequent biosynthesis steps.…”

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confidence: 99%

A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

et al. 2018

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abc Non-ribosomal peptides contain an array of amino acid building blocks that can present challenges for the synthesis of important intermediates. Here, we report the synthesis of glycopeptide antibiotic (GPA) thioester peptides that retains the crucial stereochemical purity of the terminal phenylglycine residue, which we show is essential for the enzymatic GPA cyclisation cascade.Non-ribosomal peptide synthesis is central to the biosynthesis of many compounds of medical importance, including a large number of antibiotics. [1][2][3][4] Due to the modular structure of nonribosomal peptide synthetases (NRPSs) -comprising repeating domains performing specific catalytic functions -and their non-dependence on the ribosome, NRPS assembly lines are able to synthesise peptides from a wide range of amino acids. 1,3This feature, combined with the extensive incorporation of (D)-amino acids and large range of further structural modifications, contribute to the extensive diversity of natural NRPS-peptides. 1,2Given the complexity of many of these compounds that are of medical interest -such as the glycopeptide antibiotics ( Fig. 1), with vancomycin and teicoplanin as representative members -there is a need to characterise NRPS biosynthesis in order to explore the possibilities for compound development through redesigning the corresponding biosynthetic machinery. [1][2][3][4] In this regard, GPAs are perfect examples: total synthesis is highly challenging, meaning that all GPAs in clinical use stem from bacterial production in vivo and modified GPAs generated via total synthesis are not always accessible for the use in clinics. 4,5 The main reasons for this synthetic complexity are the high content of racemisation-prone phenylglycine residues as well as the highly crosslinked structure of GPAs (vancomycin:, which is formed by cytochrome P450 (Oxy) enzymes that interact with the unique NRPS domain found in GPA biosynthesis, the X-domain. 4,6,7 Fig. 1 GPA cyclisation in vitro is enabled by diastereomerically pure phenylglycine thioester peptides: teicoplanin seq. 5: R 1 = 4-Hpg; R 2 = Cl; R 3 = 3,5-Dpg; pekiskomycin seq. 6: R 1 = CH 3 ; R 2 = H; R 3 = Glu; actinoidin seq. 7: R 1 = 4-Hpg; R 2 = H; R 3 = Phe; vancomycin seq. 8: R 1 = Leu; R 2 = Cl; R 3 = Asn. PCP -peptidyl carrier protein domain, X -Oxy recruitment domain, A tei -OxyA from the teicoplanin system, B van -OxyB from the vancomycin system.

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“…Next, HOPhGly 3.10 was coupled using the conditions described by Liang and coworkers utilizing COMU and 2,6-lutidine as coupling agents. 110 This reaction went smoothly, and no epimerization could be detected upon HPLC analysis of this peptide. This resin bound tripeptide 3.28 was elongated through Fmoc SPPS, producing peptide 3.29, and then (2S,3R)-3-propyloxirane-2-carboxylic acid 3.11 was attached using DIC/HOBt as coupling agents which gave unbranched peptide 3.30.…”

Section: Fmoc Spps Of Cda3a and Cda4amentioning

confidence: 94%

“…This observation had already been reported in 2017 by Liang et al who determined that HOPhGly residues could be coupled using COMU in combination with 2,6-lutidine without any appreciable epimerization. 110 The turn-inducing nature of dehydroamino acids promotes the formation of DKP which is exacerbated during basic Scheme 3.3. The synthesis of CDA3a and CDA3a analogs by Chen et al 55 Scheme 3.4.…”

Section: Biosynthetic and Chemical Synthesis Of Cda Analogsmentioning

confidence: 99%

Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block

2021

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Phenylglycine racemization in Fmoc-based solid-phase peptide synthesis: Stereochemical stability is achieved by choice of reaction conditions

Cited by 48 publications

References 23 publications

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block

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